Epigenome-wide association study of diabetic chronic kidney disease progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE230652 | GEO | 2023/05/10
REPOSITORIES: GEO
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Project description:Chronic kidney disease (CKD) is one of the major global health problems with high incidence, poor prognosis and high medical cost. However, few pharmacological options are available for CKD. Metformin is widely used for treatment of type-2 diabetes, but recent works showed that metformin ameliorates tumor progression, inflammatory disease and tissue fibrosis. Whether metformin ameliorates non-diabetic chronic glomerular disease and CKD is unexplored. Here we showed that metformin or losartan (used as control) has protective effects against CKD by suppressing proteinuria, renal inflammation, fibrosis and glomerular injury in Alport syndrome mouse model, which spontaneously manifests chronic glomerular and kidney disease. Transcriptome analysis showed that metformin and losartan influenced molecular pathways of metabolism and inflammation, respectively. While metformin specifically affected genes that were classified as metabolic regulators, losartan specifically altered genes that were classified as inflammatory regulators. Metformin also induced multiple signaling pathways not affected by losartan. Overall, metformin ameliorates non-diabetic chronic glomerular diseases, and could be considered a therapeutic option for CKD. We used microarrays to investigate the global gene expression underlying the protective effects of metformin on Alport syndrome mice model
2021-01-30 | GSE109861 | GEO
Project description:Chronic kidney disease (CKD) is characterized by a slow and gradual loss of kidney function, with glomerular filtration loss over months or years, inevitably leading to end-stage renal disease. The renal failure resulting from this irreversible process derives from fibrotic lesions of each compartment of the kidney; glomerulosclerosis, vascular sclerosis, and tubulointerstitial fibrosis. Nevertheless, despite numerous research efforts, both the definitive mechanism underlying the progression from CKD to end stage renal disease and an effective treatment have remained elusive. In this study, We utilized TMT-multiplexed quantitative proteomics approaches to identify protein expression changes associated with chronic injury in primary cultured renal cells.
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Project description:Primary objectives: The main objective of this trial is to evaluate the efficacy and safety of the medicinal product TachoSil to reduce the degree of stenosis of the ureteres in patients undergoing radical cystectomy for bladder cancer and non-malignant conditions. As TachoSil is not registered for this use, a pilot study is chosen as an initial evaluation of the use in urological surgery.
The primary measurement will be assessment of kidney function at follow up relative to kidney function at inclusion. Kidney function will be evaluated by means of intravenous renography and GFR (glomerular filtration rate). A reduction in kidney function of 10% in one side measured by renography will be regarded as indicative of ureteral stenosis and a reduction of GFR 25% will indicate bilateral reduction/stenosis. . The kidney function will be assessed by intravenous renography and Glomerular Filtration Rate (GRF) at follow up after 2-3 months and 1 year after discharge.
Primary endpoints: The primary measurement will be assessment of kidney function at follow up relative to kidney function at inclusion. Kidney function will be evaluated by means of intravenous renography and GFR (glomerular filtration rate). A reduction in kidney function of 10% in one side measured by renography will be regarded as indicative of ureteral stenosis and a reduction of GFR 25% will indicate bilateral reduction/stenosis. . The kidney function will be assessed by intravenous renography and Glomerular Filtration Rate (GRF) at follow up after 2-3 months and 1 year after discharge. These two tests are chosen for evaluation of kidney function as they are the tests with a high level of evidence. All patients with reduced kidney function shown in one or both tests will be evaluated whether the reduction is caused by stenosis or other reasons (infections etc.).
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Project description:Kidney diseases including acute kidney injury (AKI) and chronic kidney disease (CKD), which can progress to end stage renal disease (ESRD), are a worldwide health burden. Organ trans-plantation or kidney dialysis are the only effective available therapeutic tools. Therefore, in vitro models of kidney diseases and the development of prospective therapeutic means are highly demanded. Within the kidney, the glomeruli are involved in blood filtration and waste excre-tion, and are easily affected by changing cellular conditions. Puromycin aminonucleoside (PAN) is a nephrotoxin, which can be harnessed for imitating acute glomerular damage and modelling of glomerular disease. For this reason, we generated kidney organoids from three iPSC lines and treated these with PAN in order to induce kidney injury. Morphological observations re-vealed disruption of glomerular and tubular structures within the kidney organoids upon PAN treatment, which were confirmed by transcriptome analyses. Subsequent analyses revealed an upregulation of immune response as well as inflammatory and cell death-related processes. We concluded that treatment of iPSC-derived kidney organoids with PAN induces kidney injury mediated an intertwined network of inflammation, cytoskeletal re-arrangement, DNA damage, apoptosis and cell death. Furthermore, urine stem cell-derived kidney organoids can be used for modelling of kidney-associated diseases and drug discovery.
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Project description:Epidemiological studies indicate that adverse intrauterine and postnatal environment has a long-lasting role in chronic kidney disease (CKD) development. Epigenetic information can represent a plausible carrier for mediating this programming effect. Here we demonstrate that genome-wide cytosine methylation patterns of healthy and CKD tubule samples obtained from patients show significant differences. Cytosine methylation changes showed high concordance (98%) with a large (n=87) replication dataset. We rarely observed differentially methylated regions (DMR) on promoters. Histone modification-based kidney specific genome-wide gene regulatory region annotation maps (promoters, enhancers, transcribed and repressed regions) were generated. DMRs mostly overlapped with putative enhancer regions and were enriched in consensus binding sequences for important renal transcription factors, indicating their importance in gene expression regulation. A core set of genes, including transforming growth factors and collagens, showed cytosine methylation changes correlating with downstream transcript levels. Our report raises the possibility that epigenetic dysregulation plays a role in CKD development via influencing core profibrotic pathways. We used microarrays to detail the differences of gene expression of human tubule epithelial cells between chronic kidney disease and normal. We sought to decrease the cell type heterogeneity of kidney tissues to increase the resolution of expression profiles. To that end, microdissected human kidney tissue from both chronic kidney disease patient and normal are used for RNA extraction and hybridization on Affymetrix microarrays.
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